A straightforward entry into polyketide monoprenylated furanocoumarins and pyranocoumarins

Article abstract of DOI:10.1021/np990241o

A regioselective synthesis of 5-methyl- and 5-ethyl-4- hydroxycoumarin (1b and 1c, respectively) is described. Starting from these compounds, several prenylated polyketide coumarins of limited availability from natural sources and important taxonomic relevance were prepared.

Full text of DOI:10.1021/np990241o

J . Nat. Prod. 1999, 62, 1627-1631
1627
A Str a igh tfor w a r d En tr y in to P olyk etid e Mon op r en yla ted F u r a n ocou m a r in s
a n d P yr a n ocou m a r in s1
Giovanni Appendino,† Giancarlo Cravotto,*,† Giovanni B. Giovenzana,§ and Giovanni Palmisano*,‡
Dipartimento di Scienza e Tecnologia del Farmaco, Facolta` di Farmacia, via Giuria 9, 10125 Torino, Italy,
Dipartimento di Chimica Organica e Industriale, via Venezian 21, 20135 Milano, Italy, and
Dipartimento di Scienze Mediche, Facolta` di Farmacia, viale Ferrucci 33, 28100 Novara, Italy
Received May 21, 1999
A regioselective synthesis of 5-methyl- and 5-ethyl-4-hydroxycoumarin (1b and 1c, respectively) is
described. Starting from these compounds, several prenylated polyketide coumarins of limited availability
from natural sources and important taxonomic relevance were prepared.
Coumarin derivatives are widespread in nature, espe-
cially in higher plants,2 and the coumarin system is a
versatile template, amenable by appropriate molecular
decoration to a great variety of applications within the
realm of pharmaceuticals,3 asymmetric syntheses,4 and
chiral separations.5 Many biologically active coumarins
bear an oxygen function at C-4, with pre-eminent examples
being the hemorrhagic toxin ferulenol6 and the topo-
isomerase inhibitor novobiocin7 from plant and mold
sources, respectively.8 In sharp contrast to 7-hydroxycou-
marins, 4-hydroxycoumarins can originate either from the
shikimate or from the polyketide route,9 and the presence
of a substituent at C-5 (methyl-, ethyl-) is the hallmark of
this pathway. Although 4-hydroxycoumarin (1a ) is an
inexpensive commercial chemical, its 5-methyl- and 5-ethyl-
derivatives (1b and 1c) are only available through multi-
step, low-yielding, and generally nonregioselective synthe-
ses.10
Polyketide coumarins have a narrow distribution in
plants and are almost invariably prenylated. The attach-
ment is generally bidentate, resulting in the formation of
a pyranocoumarin or a furanocoumarin system. These
compounds are common within the Mutisieae tribe of the
Compositae families2c,d but are otherwise very rare and,
therefore, of exceptional taxonomic value.11 The structural
complexity of polyketide coumarins has sparked intense
synthetic activity culminating in several elegant syntheses,
mainly by Bohlmann’s group.12 Paradoxically, many sim-
pler members of the class have never been synthesized.
This is even more surprising when one considers that these
compounds, available by isolation only in minute amounts,
are the most useful from a chemotaxonomic point of view,
having been found also in the “difficult” and complex family
of the Meliaceae.11 The pharmacology of these compounds
is virtually unexplored, notwithstanding their isolation
from plants used in traditional medicine13 and the powerful
antiprotozoal activity displayed by certain sesquiterpene
polyketide coumarins.14
prenyl building blocks to afford, after further modification,
all of the core pyranocoumarins and furanocoumarins of
the monoprenyl type. Their corresponding 5-nor deriva-
tives, hitherto unknown as natural products, were also
synthesized for comparison.
Resu lts a n d Discu ssion
Ethyl 6-methyl-(2b) and 6-ethylsalicylate (2c) were
identified as suitable starting materials for the synthesis
of 1b and 1c, respectively. Compounds 2b and 2c are not
commercially available, but an expeditious procedure for
the preparation of 2a from crotonaldehyde and ethyl
acetoacetate via Robinson annulation and aromatization
has been reported (Scheme 1).15 We modified the reported
procedure (see Experimental Section) and extended it to
the preparation of 2c by replacement of crotonaldehyde
with its homologue (pent-2-enal). 4-Hydroxy-5-methylcou-
marin (1b) was next prepared by reacting 2b with the
lithium enolate of tert-butyl acetate (Rathke salt),16 gener-
ated in the presence of an excess LDA (lithium diisopro-
pylamide) to avoid its re-protonation by the phenolic
hydroxyl of 2b. After considerable optimization, a protocol
employing 5.5 equiv LDA and 3.5 equiv Rathke salt was
established. The excess tert-butyl acetate is necessary to
suppress the formation of N,N-diisopropyl-6-methylsalicy-
lamide, the result of competitive nucleophilic attack by
LDA on the ester carbonyl of 2b. The use of alternate
hindered bases (LiHDMS, LiTMP) did not substantially
increase the yield. The crude Claisen adduct 3a was next
stirred with neat trifluoroacetic acid to affect the cyclization
to 1b, eventually obtained in overall 85% yield from 2b. A
similar procedure from 2c afforded 1c in comparable yield.
The methyl group of 2b provided a handle for function-
alization, paving the way to chain extension. As an example
of these possibilities, an alternate preparation of 2c, using
2b as the starting material, was executed. Thus, after
protection of the phenolic hydroxyl of 2b as a BOC
(butoxycarbonyl) derivative and metalation with LDA in
the presence of TMEDA (N,N,N′-trimethylenediamine),17
the deep-orange solution of the 6-lithiomethyl anion of
BOC-protected 2b was quenched with methyl iodide.
Deprotection with neat formic acid afforded directly 2c.
The availability of an expeditious synthesis of these
compounds should prompt a systematic investigation on
their occurrence and pharmacological potential. With this
aim in mind, we have developed a straightforward synthe-
sis of 5-methyl- and 5-ethyl-4-hydroxycoumarins. These
compounds were then reacted with commercially available
With a source of 1b and 1c secured, we moved on to the
introduction of the prenyl residues. The synthesis of the
pyranocoumarins 4a -c capitalized on a domino Knoev-
enagel-electrocyclic reaction, using 3-methyl-2-butenal as
a bidentate prenyl synthon.18 Thus, starting from 4-hy-
droxycoumarin and its 5-methyl and 5-ethyl derivatives,
* To whom correspondence should be addressed. Tel.: +39 011 670 7684
(GC). Fax: +39 011 670 7687 (GC). E-mail: cravotto@pharm.unito.it (GC).
† Dipartimento di Scienza e Tecnologia del Farmaco.
§
Dipartimento di Chimica Organica e Industriale.
Dipartimento di Scienze Mediche.
‡
10.1021/np990241o CCC: $18.00
© 1999 American Chemical Society and American Society of Pharmacognosy
Published on Web 10/28/1999

1628 J ournal of Natural Products, 1999, Vol. 62, No. 12
Appendino et al.
Sch em e 1. Synthesis of 5-Methyl- and
5-Ethyl-4-hydroxycoumarin (1b,c)
Sch em e 3. Synthesis of the Furanocoumarins 7a ,b and 8a ,b
Sch em e 2. Synthesis of the Pyranocoumarins 4a -c and 5a ,b
spur studies aimed at a better evaluation of their puzzling,
scattered distribution in plants and of their biological
activity.
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. Anhydrous condi-
tions were achieved (when indicated) by flame-drying flasks
and equipment. Reactions were monitored by TLC on Alugram
Sil-Macherey Nagel (F254, 0.25 mm) plates, and spots were
detected by UV inspection or staining with 5% aqueous KMnO4
or 5% H2SO4 in EtOH and heating. Merck Si gel was used for
open-column chromatography and MPLC (70-230 mesh and
230-440 mesh, respectively). MPLC was carried out on a
Bu¨chi instrument B 680A, equipped with a B 685-type column.
Waters microPorasil 7.8-300 and Merck Hibar 25-250 col-
umns were used for semipreparative HPLC, with detection by
a Gilson 133 refractive index refractometer. Melting points
were obtained on a Bu¨chi SMP-20 apparatus and are uncor-
nor-bothrioclinin (4a ), bothrioclinin (4b),19 and homo-
bothrioclinin (4c)19 were obtained (Scheme 2). The spec-
troscopic data on 4b and 4c were identical to those reported
for the natural products.19 Ytterbium triflate proved su-
perior to the Tietze base (diethylendiammonium diacetate)
to promote the reaction.20 Catalytic hydrogenation of the
pyranocoumarin adducts afforded the corresponding 2,3-
dihydroderivatives, one of which is known as a natural
product (pterophyllin III, 5b).11
1
rected. H NMR (300 and 200 MHz) and 13C NMR (75 MHz)
spectra were recorded on a Bruker AC-300 and Bruker AC-
To synthesize the prenylated coumarins of the furano-
type, we relied on the cerium [IV]ammonium nitrate
(CAN)-mediated oxidative addition of 1a ,b to 2-methyl-3-
buten-2-ol (Scheme 3).21 The reaction was regioselective in
the carbon-carbon-forming step, but poorly discriminating
in the following carbon-oxygen-formation step, because the
oxygen of both the ketone- and the lactone-carbonyl could
be involved. As a result, a mixture of linear (6a ,b) and
angular adducts (7a ,b) was obtained (Scheme 3). These
compounds were easily separated by column chromatog-
raphy, with the linear adduct being eluted first from Si
gel column chromatography in all cases. The spectroscopic
assignment of 6a ,b and 7a ,b relied on diagnostic differ-
ences in the chemical shift of the atom at C-5 (deshielding
peri-effect of the ketone carbonyl in the linear adducts 7a ,b)
and in the frequency of the carbonyl stretching (lactone vs
enone).21,22 Compound 6b was identical to the natural
product isoerlangeafusciol.23 The adducts from the furano
series could be regioselectively dehydrated using either the
Burgess24 or the sulfurane Martin reagent.25 In this way
pterophyllin I (8b)11 as well as its nor-derivative (8a ), yet
unreported as a natural product, could be obtained.
In conclusion, a straightforward entry into the most
elementary members of the pyrano- and furano-polyketide
prenylated coumarins has been achieved. The increased
availability of these important taxonomic markers should
1
200 spectrometers at 25 °C. H and 13C NMR chemical shifts
refer to CHCl3 at 7.26 ppm, and CDCl3 at 77.0 ppm, respec-
tively. LRMS were performed on a Finnigan-MAT TSQ70 in
chemical ionization with isobutane as reactant gas. Com-
mercially available reagents and solvents were used without
further purification unless otherwise stated. CH2Cl2 was dried
by distillation from P4O10 and THF by distillation from Na-
benzophenone.
Eth yl 6-Meth ylsa licyla te (2b). The condensation between
ethyl acetoacetate (132 mL, 1.04 mol) and crotonaldehyde (85.8
mL, 1.04 mol) in the presence of sodium ethoxide (30 mmol)
was carried out according to Hauser and Pogany15a. After the
aromatization with CuCl2 and LiCl in DMF at 90 °C, the dark
brown reaction mixture was cooled to room temperature,
diluted with ice-water and poured on a Celite-Si gel bed
previously prepared on a sintered glass funnel (180 mm, 100
g Celite and 150 g Si gel). After filtration with suction and
washing with H2O (1 L) to remove DMF, 2b was eluted with
petroleum ether. Further purification was achieved with
fractional distillation under vacuum (80 °C, 0.66 kPa) and a
normal air condenser, occasionally heated to avoid clogging
from lumps of solidified distillate. Compound 2b (86 g, 46%)
was obtained as pale yellow crystals; 2b could alternatively
be purified by MPLC (petroleum ether-EtOAc 95:5): Rf
(hexane-EtOAc 7:3) 0.64.
Eth yl 6-Eth ylsa licyla te (2c). To a cooled (0 °C) two-necked
round-bottomed flask, equipped with a pressure-equalizing
addition funnel, magnetic stirrer, and nitrogen inlet, 37.8 mL

Prenylated Polyketide Coumarins
J ournal of Natural Products, 1999, Vol. 62, No. 12 1629
(287 mmol) of ethyl acetoacetate and 57 mL of sodium ethoxide
(8.57 mmol) in EtOH were sequentially added. 2-Pentenal (29
mL, 0.297 mmol) was then added over 5 min. After stirring
30 min at 0 °C, the solution was allowed to warm to room
temperature for 48 h, and saturated by bubbling HCl (15 min
at 0 °C). After stirring two further days at room temperature,
the solution was freed of HCl by stripping under vacuum
(water pump) and mild heating. The dark brown residue
obtained in this way was dissolved in DMF (50 mL) and heated
at 90 °C under magnetic stirring. Then, 32.93 g (0.297 mol)
CuCl2 and 17.30 g (0.408 mol) LiCl were added, and the flask
was immediately connected to a Drechsel bottle containing 3N
NaOH. After 3 h, the dark reaction mixture was cooled to room
temperature and treated as described for 2b. The crude
reaction mixture was purified by column chromatography
using petroleum ether as the eluent, affording 31 g of 2c (54%)
as a straw-colored oil: IR (liquid film) 3350, 1662, 1608, 1451,
(c) Deprotection. A mini-vial was charged with ethyl 2-BOC-
6-ethylsalicylate (1.0 g, 3.4 mmol) and HCO2H (1 mL) and left
for 4 h in the refrigerator at 5 °C. The solution was then poured
into ice-water (50 mL), neutralized with NaHCO3, and ex-
tracted with EtOAc. The organic layer was washed with brine
(80 mL), dried (MgSO4), filtered, and evaporated. The residue
was purified by column chromatography (20 g Si gel, petroleum
ether-EtOAc 19:1 as eluent) to give 606 mg (92%) of 1c.
4-Hyd r oxy-5-m eth ylcou m a r in (1b). To a 200-mL three-
necked round-bottomed flask equipped with a pressure-equal-
izing addition funnel, magnetic stirrer, nitrogen inlet, and a
thermometer, diisopropylamine (7.08 mL, 50.48 mmol), N-
benzylbenzamide (5 mg), and dry THF (20 mL) were added.
The solution was cooled (-78 °C), and n-BuLi (1.6M in
hexanes, 30.1 mL, 48.15 mmol) was added slowly. After 30
min, a solution of tert-butyl acetate (3.56 g, 30.62 mmol, 3.5
mol. equiv.) in 10 mL of THF was added over 5 min, during
which time the solution turned from dark blue to deep yellow.
The solution was then stirred at -78 °C for 50 min, and a
solution of ethyl 6-methylsalicylate (2b) 1.68 g (8.75 mmol) in
10 mL THF was added over 5 min. After warming to room
temperature overnight, the reaction was quenched by the
addition of ice-cooled saturated aqueous NH4Cl (50 mL) and
EtOAc (80 mL). The organic layer was washed with brine (100
mL), dried (MgSO4), and concentrated. The residue was
purified by medium-pressure column chromatography (40 g
Si gel; packing with petroleum ether, followed by petroleum
ether-EtOAc 9:1) to afford 319 mg (19%) of recovered ethyl
6-methylsalicylate (2b) and 942 mg (71%) of 3b as pale-yellow
1
1248, 1209 cm-1; H NMR (CDCl3) δ 11.25 (1H, s, OH), 7.32
(1H, t, J ) 7.9 Hz, H-4), 6.86 (1H, d, J ) 7.9 Hz, H-5), 6.75
(1H, d, J ) 7.9 Hz, H-3), 4.46 (2H, q, J ) 7.1 Hz, CH2-1′), 2.97
(2H, q, J ) 7.4 Hz, H-7), 1.45 (3H, t, J ) 7.1 Hz, CH3-2′), 1.23
(3H, t, J ) 7.4 Hz, H-8);13C NMR (CDCl3) δ 171.4 (s, CdO),
162.35 (s, C-2), 147.40 (s, C-6), 134.13 (d, C-4), 121.57 (d, C-5),
115.49 (d, C-3), 111.83 (s, C-1), 61.52 (t, C-1′), 29.49 (t, C-7),
16.15 and 13.90 (2 q, C-2′ and C-8); LRMS 195 (MH+, CIMS);
Rf (hexane-EtOAc 9:1) 0.57; anal. calcd for C11H14O3; C 68.02,
H 7.26; found C 67.99, H 7.28.
Eth yl 6-Eth ylsa licyla te by Hom ologa tion of 2b. (a)
Protection of the phenolic hydroxyl. In a two-necked round-
bottomed flask equipped with magnetic stirrer and nitrogen
inlet, 2b (6.312 g, 35 mmol) was dissolved in 30 mL of
anhydrous CH2Cl2 at room temperature. To this solution, 7.19
mL (42.07 mmol) N-ethyl diisopropylamine (Hu¨nig base), 9.191
g (42.07 mmol) di-(t-butyl)dicarbonate, and a few crystals
DMAP (4-(dimethylamino)pyridine) were added. After stirring
overnight, the reaction was diluted with 100 mL of CHCl3,
washed with 2N HCl (3 × 50 mL) and brine (2 × 50 mL), and
dried over MgSO4. Removal of the solvent left a yellow oil,
purified by column chromatography (100 g Si gel, petroleum
ether-EtOAc 19:1 as eluent) to afford 9.52 g (97% yield) of a
pale yellow oil: IR (liquid film) 1763, 1731, 1468, 1379, 1235,
oil: IR (liquid film) 2980, 1730, 1455, 1148, 1034, 781 cm-1
;
1H NMR (CDCl3) δ 10.85 (br s, 1H, OH), 7.27 (1H, t, J ) 7.5
Hz, H-4), 6.83 (1H, d, J ) 7.5 Hz, H-5), 6.73 (1H, d, J ) 7.5
Hz, H-3), 3.91 (2H, s, CH2CO), 2.53 (3H, s, H-7), 1.45 (9H, s,
t-Bu); LRMS 251 (MH+); Rf (hexane-EtOAc 9:1) 0.64; anal.
calcd for C14H18O4; C 67.18, H 7.25; found C 67.53, H 7.21.
When 1.2 equiv tert-butyl acetate was used, the yield
dropped to 19%, and N,N-di(isopropyl)-6-methyl salicylamide
was also isolated in 15% yield as colorless needles: mp 212-
214 °C; IR (KBr) 2950, 2693, 1600, 1575, 1460, 1369, 1298,
1038, 785 cm-1; H NMR (CDCl3) δ 8.58 (1H, br s, 1H, OH),
1
6.66 (1H, t, J ) 7.8 Hz, H-4), 6.33 (2H, m, J ) 7.8 Hz, H-3
and H-5), 3.40 and 3.18 (2H, br s, R-CH-Me2), 1.89 (3H, s,
Me-aryl), 1.23 (6H, br s, Me2-CHR), 0.81 (6H br d, J ) 7.0
Hz, Me2-CHR); LRMS 236 (MH+); Rf (hexane-EtOAc 3:7)
0.58; anal. calcd for C14H21NO2; C 71.46, H 8.99, N 5.95; found
C 71.39, H 8.96, N 5.92. A mini-vial was charged with 3b (1.0
g, 4 mmol) and trifluoroacetic acid (0.5 mL). The mixture was
shaken vigorously (10 min) and allowed to settle at room
temperature for 4 h. A pale yellow solid formed, which was
collected on a sintered glass filter and washed with a 3:1
mixture of petroleum ether and Et2O (20 mL). The filtrate was
concentrated and cooled (4 °C) to afford a second crop of 1b as
a yellowish powder. The overall yield was (584 mg) 83%: mp:
229-230 °C [lit.26 221-223 °C]; IR (KBr) 3384, 1649, 1559,
1344, 1262, 820 cm-1; 1H NMR (CDCl3) δ 12.41 (1H, br s, OH),
7.46 (1H, t, J ) 7.9 Hz, H-7), 7.17 (1H, d, J ) 8.1 Hz, H-6),
7.09 (1H, d, J ) 7.5, H-8), 5.56 (1H, s, H-3), 2.66 (3H, s, Me);
13C NMR (CDCl3) δ 161.5 (s, C-2), 91.3 (d, C-3), 168.7 (s, C-4),
114.4 (s, C-4a), 137.2 (s, C-5), 127.2 (d, C-6), 131.8 (d, C-7),
114.9 (d, C-8), 155.1 (s, C-8a), 22.8 (q, C-9); LRMS 177 (MH+);
Rf (CHCl3-MeOH-H2O 8:1:1) 0.75; anal. calcd for C10H8O3;
C, 68.16, H 4.58; found C 68.20, H 4.5.
1
1152, 872 cm-1; H NMR (CDCl3) δ 7.33 (1H, t, J ) 7.8 Hz,
H-4), 7.11 (1H, d, J ) 7.8 Hz, H-5), 7.03 (1H, d, J ) 8.1 Hz,
H-3), 4.38 (2H, q, J ) 7.2 Hz, CH2-1′), 2.42 (3H, s, H-7), 1.53
(9H, s, t-Bu), 1.39 (3H, t, J ) 7.1 Hz, H-2′); LRMS 281 (MH+,
CIMS); Rf (hexane-EtOAc 8:2) 0.35.
(b) Homologation. To a 100-mL, three-necked round-bot-
tomed flask equipped with a pressure-equalizing addition
funnel, magnetic stirrer, nitrogen inlet, and a thermometer,
dry THF (10 mL), TMEDA (650 µL, 4.37 mmol), diisopropyl-
amine (775 µL, 8.63 mmol), and N-benzylbenzamide (3 mg)
were added. The solution was cooled (-78 °C), and n-BuLi
(1.6M in hexanes, 5.16 mL, 8.22 mmol) was added slowly. After
30 min, a solution of 1.441 g (5.14 mmol) ethyl 2-O-BOC-6-
methylsalicylate in 10 mL of THF was added over 5 min,
during which the solution turned from dark blue to red and
then to orange. The solution was then stirred at -78 °C for
40 min, and a solution of methyl iodide (2.56 mL, 41.12 mmol)
in THF (5 mL) was added, causing the reaction mixture to
turn yellow. The solution was allowed to warm to room
temperature overnight, and then quenched by the addition of
ice-cooled saturated aqueous NH4Cl (40 mL) and EtOAc (40
mL). The organic layer was washed with brine (50 mL), dried
(MgSO4), filtered, and then concentrated under reduced pres-
sure. The crude yellow oil obtained in this way was purified
by column chromatography (25 g Si gel, petroleum ether-
EtOAc 19:1 as eluent) to afford 1.027 g (68%) ethyl O-2-BOC-
6-ethylsalicylate as a colorless oil: IR (liquid film) 1768, 1735,
4-Hyd r oxy- 5-eth ylcou m a r in (1c). The same procedure
described for the preparation of 1b from 2c was employed.
Compound 1c was obtained in 60% overall yield. Data for
(3c): colorless oil, IR (KBr) 3400, 1732, 1698, 1466, 1323, 1286,
1
1255, 1152 cm-1; H NMR (CDCl3) δ 7.24 (1H, t, J ) 7.8 Hz,
H-4), 6.82 and 6.79 (2 × 1H, 2 × d, J ) 8.0 Hz, H-3 and H-5),
3.89 (2H, s, H-10), 2.74 (2H, q, J ) 7.6 Hz, H-4), 1.42 (9H, s,
t-Bu), 1.29 (3H, t, Me); 13C NMR (CDCl3) δ 205.2 (s, C-9), 132.8
(d, C-4), 120.8 and 114.9 (d, d, C-3 and C-5), 51.8 (t, C-10),
27.75 (q, C- tBu), 27.1 (t, C-7), 15.9 (q, C-8); LRMS 264 (MH+,
CIMS); Rf (hexane-EtOAc 9:1) 0.52; anal. calcd for C15H20O4;
C 68.16, H 7.63; found C 68.10, H 7.69. Data for Compound
1c: IR (KBr) 3380, 1638, 1597, 1344, 1302, 821 cm-1; 1H NMR
1460, 1369, 1281, 1236, 1185, 733 cm-1 1H NMR (CDCl3
; δ
7.35 (1H, t, J ) 7.9 Hz, H-4), 7.13 (1H, d, J ) 7.3 Hz, H-5),
7.03 (1H, d, J ) 8.3 Hz, H-3), 4.38 (2H, q, J ) 7.1 Hz, CH2-1′),
2.72 (2H, q, J ) 7.5 Hz, H-7), 1.53 (3H, s, t-Bu), 1.37 (3H, t, J
) 7.0 Hz, H-8); 1.23 (3H, t, J ) 7.5, H-2′); LRMS 295 (MH+,
CIMS); Rf (hexane/EtOAc 8:2) 0.46.

1630 J ournal of Natural Products, 1999, Vol. 62, No. 12
Appendino et al.
(CDCl3) δ 12.37 (1H, br s, OH), 7.45 (1H, t, J ) 7.8 Hz, H-7),
7.13 (1H, d, J ) 7.8 Hz, H-6), 7.07 (1H, d, J ) 7.8 Hz, H-8),
5.57 (1H, s, H-3), 3.08 (2H, q, J ) 7.4 Hz, H-9), 1.18 (3H, t,
H-10); 13C NMR (CDCl3) δ 168.32 (s, C-4), 161.56 (s, C-2),
155.16 (s, C-8a), 143.61 (s, C-5), 131.82 (d, C-7), 125.96 (d, C-6),
114.82 (d, C-8), 113.70 (s, C-4a), 91.59 (d, C-3), 28.31 (t, C-9),
16.74 (q, C-10); LRMS 191 (MH+, CIMS); Rf (CHCl3-MeOH-
H2O 8:1:1) 0.75; anal. calcd for C11H10O3; C 69.46, H 5.30; found
C 69.48, H 5.22.
3-buten-2-ol (98 mg, 1.14 mmol). The suspension was cooled
to 0 °C, and a solution of CAN (1.557 g, 2.84 mmol) in MeCN
(15 mL) was added. After stirring 1 h at 0 °C, the reaction
mixture was diluted with 30 mL of H2O and extracted with
EtOAc (3 × 15 mL). The combined organic layers were washed
with saturated aqueous Na2CO3 (20 mL) and brine (20 mL).
After drying (MgSO4) and removal of the solvents, the dark
residue was purified by column chromatography (20 g Si gel,
hexanes-EtOAc 7:3 as eluent) to provide, in order of elution,
133 mg (45%) isoerlangeafusciol (7b) as colorless solid, and
its linear isomer (allo-isoerlangeafusciol, 6b ) (48 mg, 21%).
Data for 7b: IR (KBr) 3432, 1693, 1603, 1485, 1169, 1057,
2,2,10-Tr im eth yl-2H,5H-p yr a n o [3,2-c][1]ben zop yr a n -
5-on e (Both r ioclin in , 4b). 4-Hydroxy-5-methylcoumarin (1b)
(200 mg, 1.14 mmol) and 3-methyl-2-butenal (120 µL, 1.25
mmol) were dissolved in MeOH (5 mL), and a catalytic amount
of diethylendiammonium diacetate (5 mg) was added. The
reaction was stirred for 3 h at room temperature. Removal of
the solvent left an oily residue, then purified by column
chromatography (15 g Si gel, petroleum ether-EtOAc 8:2) to
afford 200 mg 4b (73%) as a white powder: mp 135-137 °C
(diethyl ether); IR (KBr) 1713, 1595, 1464, 1234, 1055, 980,
799 cm-1 1H NMR (CDCl3) δ 7.42 (1H, t, J ) 8.0 Hz, H-7),
;
7.18 (1H, d, J ) 8.0 Hz, H-8), 7.03 (1H, d, J ) 8.0 Hz, H-6),
4.91 (1H, t, J ) 9.6 Hz, H-2), 3.10 (2H, d, J ) 9.6 Hz, H-3),
2.68 (3H, s, Me-9), 2.0 (1H, br s, OH), 1.48 (s) and 1.43 (s)
(6H, Me2-C); 13C NMR (CDCl3) δ 92.7 (d, C-2), 27.0 (t, C-3),
102.7 (s, C-3a), 166.5 (s, C-4), 155.7 (s, C-5a), 117.2 (d, C-6),
135.7 (d, C-7), 126.2 (d, C-8), 131.5 (d, C-9), 114.9 (s, C-9a),
160.5 (s, C-9b), 71.5 (s, C-1′), 25.6-24.5 (q, q, C-2′ and C-3′)
21.1 (s, C-10); LRMS 261 (MH+); Rf (hexane-EtOAc 3:7) 0.46;
anal. calcd for C15H16O4; C 69.22, H 6.20; found C 69.43, H
6.19. Data for 6b: IR (KBr) 3310, 1643, 1605, 1468, 1265, 1130,
1
871 cm-1; H NMR (CDCl3) δ 7.33 (1H, dd, J ) 8.1 Hz, J ′)
7.4, H-8), 7.14 (1H, d, J ) 8.1 Hz, H-9), 7.00 (1H, d, J ) 7.4
Hz, H-7), 6.54 and 5.36 (2H, AB syst., J ) 10.0, H-4 and H-3),
2.71 (3H, s, Me-10), 1.56 (6H, s, 6H, Me2CR2); 13C NMR (CDCl3)
δ 80.5 (q, C-2), 125 (d, C-3), 117.3 (d, C-4), 100.6 (s, C-4a), 160.7
(s, C-5), 154.0 (s, C-6a), 115.3 (d, C-7), 131.3 (d, C-8), 127.4 (d,
C-9), 137.0 (s, C-10), 114.3 (s, C-10a), 161.5 (s, C-10b), 28.4
(q, C-11), 28.4 (q, C-12), 20 (q, C-13); LRMS 243 (MH+); Rf
(hexane-EtOAc 7:3) 0.44; anal. calcd for C15H14O3; C 74.36,
H 5.82; found C 74.37, H 5.77.
1
937, 794 cm-1; H NMR (CDCl3) δ 7.40 (1H, t, J ) 7.9, H-7),
7.19 (d) and 7.13 (d) (2H, J ) 8.1, 7.4 Hz, H-6 and H-8), 4.83
(1H, t, J ) 8.9 Hz, H-2), 3.11 (2H, d, J ) 8.9 Hz, H-3), 2.88
(3H, s, Me-5), 2.31 (1H, br s, OH), 1.37 (s) and 1.28 (s) (6H,
Me2-CR2); 13C NMR (CDCl3) δ 90.7 (d, C-2),), 26.1 (t, C-3),
95.7 (s, C-3a), 177.5 (s, C-4), 121.7 (s, C-4a), 141.0 (s, C-5),
128,6 (d, C-6), 131,1 (d, C-7), 115.1 (d, C-8), 154.9 (s, C-8a),
167.3 (s, C-9a), 71.4 (s, C-10), 25.2-23.9 (q, q, C-11, C-12), 22.5
(q, C-13); LRMS 261 (MH+); Rf (hexane-EtOAc 3:7) 0.32; anal.
calcd for C15H16O4; C 69.22, H 6.20; found C 69.36, H 6.17.
2-(1-Hyd r oxy-1-m eth yleth yl)-2,3-d ih yd r ofu r o[3,2-c][1]-
ben zop yr a n -2(3H)-on e (n or -Isoer la n gea fu sciol, 7a ). This
compound and its linear isomer (6a ) were obtained from
4-hydroxycoumarin (1a ) using the same procedure employed
for the synthesis of 7b. The yield was 51% for the angular
isomer, and 24% for the linear one. Data for 7a : IR (KBr) 3432,
2,2-dimethyl-pyrano[3,2-c][1]benzopyran-5-one (4a ) was pre-
pared in a similar way from 4-hydroxycoumarin (1a ) in 77%
yield. For data, see Appendino et al.18
2,2-Dim et h yl-10-et h yl-2H ,5H -p yr a n o[3,2-c][1]b en zo-
p yr a n -5-on e (Meth ylboth r ioclin in , 4c). The same proce-
dure used to prepare 4b was employed, but 4-hydroxy-5-
ethylcoumarin (1c) was used as starting material, Yb(OTf)3
(5 mg) as the catalyst, and MeCN as the solvent. Compound
4c was obtained as colorless crystals in 87% yields; mp 83 °C;
IR (KBr) 3455, 1709, 1593, 1466, 1045, 731 cm-1 1H NMR
;
(CDCl3) δ 7.38 (1H, t, J ) 7.8 Hz, H-8), 7.15 (1H, d, J ) 7.7
Hz, H-9), 7.04 (1H, d, J ) 7.7 Hz, H-7), 6.56 (1H, d, J ) 10.0
Hz, H-4), 5.49 (1H, d, J ) 10.0 Hz, H-3), 3.11 (2H, q, J ) 7.4
Hz, H-11), 1.58 (6H, s, Me2CR2), 1.26 (3H, t, J ) 7.4 Hz, H-12);
13C NMR (CDCl3) δ 80.5 (q, C-2), 117.2 (d, C-3), 115.2 (d, C-4),
100.4 (s, C-4a), 160.9 (s, C-5), 154.4 (s, C-6a), 125.0 (d, C-7),
126.3 (d, C-8), 131.4 (d, C-9), 143.4 (s, C-10), 113.5 (s, C-10a),
169.2 (s, C-10b), 28.9 (q, C-11), 17.0 (t, C-12), 28.2 (q, C-13);
LRMS 257 (MH+, CIMS); Rf (hexane-EtOAc 7:3) 0.65; anal.
calcd for C16H16O3; C 74.98, H 6.29; found C 74.77, H 6.35.
3,4-Dih yd r o-2,2,10-tr im eth yl-2H,5H-p yr a n o [3,2-c][1]-
ben zop yr a n -5-on e (P ter op h yllin III, 5b). To a solution of
4b (100 mg, 0.41 mmol) in EtOAc (5 mL), 20% palladium
hydroxide on carbon (25 mg) was added. The flask was
evacuated and purged with dry nitrogen three times, and then
placed under an atmosphere of hydrogen (101.32 kPa). After
3 h, the reaction mixture was filtered through a pad of Celite,
and the residue was washed with EtOAc (100 mL). The filtrate
and the washings were evaporated, and the residue was
purified by column chromatography (5 g Si gel, hexane-EtOAc
19:1) to give 5b (74 mg, 75%) as a colorless solid: mp 110-
112 °C (diethyl ether) [lit.11 gum, 58-60 °C]; IR (KBr) 1699,
1618, 1443, 1323 cm-1; 1H NMR (CDCl3) δ 7.31 (1H, t, J ) 7.8
Hz, H-8), 7.14 (1H, d, J ) 7.7 Hz, H-9), 7.00 (1H, d, J ) 7.4
Hz, H-7), 2.68 (3H, s, Me-10), 2.59 (2H, t, J ) 6.7 Hz, H-3),
1.84 (2H, t, J ) 6.7 Hz, H-4), 1.44 (6H, s, Me-12 and 13); 13C
NMR (CDCl3) δ 78.1 (q, C-2), 31.4 (t, C-3), 17.5 (t, C-4), 99.3
(s, C-4a), 163.0 (s, C-5), 158.6 (s, C-6a), 115.1 (d, C-7), 130.8
(d, C-8), 127.3 (d, C-9), 138.4 (s, C-10), 114.9 (s, C-10a), 161.8
(s, C-10b), 23.5 (q, C-11), 26.7 (q, C-12 and q, C-13); LRMS
245 (MH+); Rf (hexane-EtOAc 7:3) 0.47; anal. calcd for
1709, 1647, 1418, 1032, 908, 754, cm-1 1H NMR (CDCl3) δ
;
7.66 (1H, dd, J ) 7.7 Hz, J ′) 1.5 Hz, H-9), 7.52 (1H, t, J ) 7.7
Hz, H-7), 7.32 (1H, d, J ) 7.7 Hz, H-8), 7.25 (1H, t, J ) 7.7
Hz, H-6), 4.93 (2H, t, J ) 9.4 Hz, H-3), 2.38 (1H, br s, OH),
1.38 (s), and 1.27 (s), (6H, Me2-C); 13C NMR (CDCl3) δ 93.1
(d, C-2), 27.7 (t, C-3), 102.6 (s, C-3a), 166.5 (s, C-4), 154.7 (s,
C-5a), 116.8 (d, C-6), 132.2 (d, C-7), 122.5 (d, C-8), 123.8 (d,
C-9), 112.2 (s, C-9a), 160.6 (s, C-9b), 71.5 (s, C-1′), 25.4-24.3
(q, q, C-2′ and C-3′); LRMS 247 (MH+); Rf (hexane-EtOAc 3:7)
0.45. Data for 6a : IR (KBr) 3328, 1701, 1620, 1466, 1414, 1213,
756, cm-1; 1H NMR (CDCl3) δ 7.74 (1H, m, H-5), 7.50 (1H, m,
H-7), 7.35 (1H, m, H-6), 7.28 (1H, m, H-8), 4.80 (1H, t, J ) 9.0
Hz, H-2), 3.10 (2H, d, J ) 9.0 Hz, H-3), 2.28 (1H, br s, OH),
1.33 (s) and 1.25 (s), (6H, Me2-CR2); LRMS 247 (MH+); Rf
(hexane-EtOAc 2:8) 0.34.
2-(1-Meth yleth en yl)-9-m eth yl-2,3-d ih yd r ofu r o[3,2-c][1]-
ben zop yr a n -2(3H)-on e (P ter op h yllin I, 8b): A solution of
the angular adduct (7b) (100 mg, 0.38 mmol) in anhydrous
C6H6 (4 mL) was refluxed for 30 min in the presence of Burgess
reagent (methoxycarbonylsulfamoyl-triethylammonium hy-
droxide inner salt) (100 mg, 0.42 mmol). The solution was
diluted with H2O and extracted with EtOAc, washing the
organic phase with brine and then drying it over Na2SO4. The
residue was purified by column chromatography (hexanes-
EtOAc 8:2 as eluent) to give 44.2 mg (48%) 8b as a colorless
gum: mp 58-60 °C [lit.11 61°-63 °C]; IR (KBr) 1720, 1632,
1601, 1454, 1049, 1018, 792 cm-1; 1H NMR (CDCl3) δ 7.42 (1H,
t, J ) 7.9 Hz, H-7), 7.24 (1H, d, J ) 8.3 Hz, H-8), 7.07 (1H, d,
J ) 7.5 Hz, H-6), 5.51 (1H, dd, J ) 10.4, 8.2 Hz, H-2), 5.14
(1H, s, H-2′a), 5.02 (1H, s, H-2′b), 3.33 (1H, dd, J ) 15.3, 10.6
Hz, H-3a), 2.98 (1H, dd, J ) 8.2, 15.3 Hz, H-3b), 2.70 (3H, s,
Me-1′), and 1.84 (3H, s, Me-9); 13C NMR (CDCl3) δ 89.09 (d,
C-2), 31.06 (t, C-3), 128.8 (s, C-3a), 168.3 (s, C-4), 156.0 (s,
C-4a),115.0 (d,C-6), 131.6 (d, C-7), 126.3 (d, C-8), 136.2 (s, C-9),
111.9 (s, C-9a), 163.0 (s, C-9b), 142.4(s, C-1′), 113.0 (t, C-2′),
17.1 (q, C-3′), 21.3 (s, C-10); LRMS 243 (MH+); Rf (hexane-
C
15H16O3; C 73.75, H 6.60; found C 73.78, H 6.58.
2-(1-Hydr oxy-1-m eth yleth yl)-9-m eth yl-2,3-dih ydr ofu r o-
[3,2-c][1]ben zop yr a n - 2(3H)-on e (Isoer la n gea fu sciol, 7b).
5-Methyl-4-hydroxycoumarin (1b) (200 mg, 1.14 mmol) was
suspended in dry MeCN (15 mL) in the presence of 2-methyl-

Prenylated Polyketide Coumarins
J ournal of Natural Products, 1999, Vol. 62, No. 12 1631
(7) Kaczka, E. A.; Wolf, F. G.; Rathe, F. P.; Folkers, K. J . Am. Chem.
Soc. 1955, 77, 6604-6605.
(8) Dicoumarol, the archetypal coumarin anticoagulant, is derived from
the microbial transformation of ortho-hydroxycinnamic acid and
melilotic acid and is therefore of “mixed” origin (see Murray2a pp 182-
185).
EtOAc 4:6) 0.68; anal. calcd for C15H14O3; C 74.36, H 5.82;
found C 74.40, H 5.81.
2-(1-Met h ylet h en yl)-2,3-d ih yd r ofu r o[3,2-c][1]b en zo-
p yr a n -2(3H)-on e (n or -P ter op h yllin I, 8a ). The same pro-
cedure described above, but using 7a as the starting material,
gave the title compound in 51% yield: IR (KBr) 1720, 1630,
1600, 1452, 1040, 1016, 788 cm-1; 1H NMR (CDCl3) δ 7.70 (1H,
d, J ) 7.8 Hz, H-9), δ 7.58 (1H, t, J ) 7.8 Hz, H-7), 7.40 (1H,
d, J ) 8.3 Hz, H-6), 7.30 (1H, t, J ) 7.5 Hz, H-8), 5.53 (1H,
dd, J ) 10.2 Hz, J ′ ) 8.4, H-2), 5.16 (1H, s, H-2′a), 5.02 (1H,
s, H-2′b), 3.36 (1H, dd, J ) 15.4, 10.4 Hz, H-3a), 3.02 (1H, dd,
J ) 8.1, 15.3 Hz, H-3b), 1.82 (3H, s, Me-2′); LRMS 243 (MH+);
Rf (hexane-EtOAc 4:6) 0.65; anal. calcd for C14H12O3; C 73.67,
H 5.30; found C 73.62, H 5.30.
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Ack n ow led gm en t. This work was supported by MURST
(Progetto Chimica dei Composti Organici di Interesse Bio-
logico, Fondi Ex 40%).
Refer en ces a n d Notes
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NP990241O